Certain {62 -hydroxy-{62 -phenylethyl-substituted cyclic acylureas

ABSTRACT

New mono- or dialcohols of mononuclear, five-membered or sixmembered, unsubstituted or substituted N-heterocyclic compounds which contain two NH-groups in the molecule, by reaction of mononuclear, five-membered or six-membered, unsubstituted or substituted N-heterocyclic compounds, for example hydantoin, barbituric acid, uracil, dihydrouracil, parabanic acid and the corresponding derivatives, with styrene oxide to give monoalcohols or dialcohols. These compounds are useful as intermediates for the preparation of diglycidyl compounds as set forth in the German Offenlegungsschrift No. 2,058,206.

United States Patent Habermeier et al.

CERTAIN B-HYDROXY-B-PPIENYLETHYL- SUBSTITUTED CYCLIC ACYLUREAS Inventors: Juergen Habermeier, Allschwil;

Hans Batzer, Arlesheim; Daniel Porret, Binningen, all of Switzerland Assignee: Ciba-Geigy AG, Basel, Switzerland Filed: June 13, 1972 Appl. No.: 262,421

Related US. Application Data Continuation-impart of Ser. No. 82,071, Oct. 19, I970, Pat. No. 3,686 ,l74.

Foreign Application Priority Data Nov. 27, i969 Switzerland 17672/69 US. Cl. 260/257 Int. Cl.. C07d 51/20, C07d 5l/30, C07d 49/32 Field of Search 260/257, 309.5, 260

References Cited FOREIGN PATENTS OR APPLICATIONS 6/1970 Germany 260/257 Primary ExaminerDonald G. Daus Assistant Examiner-Anne Marie T. Tighe 5 7] ABSTRACT New monoor dialcohols of mononuclear, fivemembered or six-membered, unsubstituted or substituted N-heterocyclic compounds which contain two Nl-l-groups in the molecule, by reaction of mononuclear, five-membered or six-membered, unsubstituted or substituted N-heterocyclic compounds, for example hydantoin, barbituric acid, uracil, dihydrouracil, parabanic acid and the corresponding derivatives, with styrene oxide to give monoalcohols or dialcohols. These compounds are useful as intermediates for the preparation of diglycidyl compounds as set forth in the German Offenlegungsschrift No. 2,058,206.

8 Claims, No Drawings CERTAIN B-HYDROXY-B-PHENYLETHYL-SUBSTITUTED CYCLIC ACYLUREAS This application is a continuation-in-part application 5 of our copending application Ser. No. 82,071, filed Oct. 19, 1970, and now US. Pat. No. 3,686,174.

The subject of the present invention are new mono or dialcohols of general formula fwd) a rn j r:

wherein Z denotes a nitrogen-free, divalent radical which is necessary for completing a five-membered or six-membered, unsubstituted or substituted, heterocy-' clic ring, and m and n each represent an integer having a value of 0 to 30, preferably of 0 to 4, with the sum of m and n having to be at least 1.

The radical Z in the formula (I) preferablyconsists only of carbon and hydrogen or of carbon, hydrogen and oxygen. It can for example be a radical of formula:

wherein Z has the same meaning formula with styrene oxide in the presence of a suitable catalyst.

The addition of styrene oxide to one or both NH groups of the N-heterocyclic compounds of formula (I!) can be carried out both in the presence of acid catalysts and of alkaline catalysts, with a slight excess of equivalents of epoxide groups of the styrene oxide being employed per equivalent of NH group of the N heterocyclic compound of formula (II).

Preferably, however, alkaline catalysts, such as tetra ethylammonium chloride or tertiary amines, are used in the manufacture of monoalcohols and dialcohols of formula (II) in which the sum of m and n is l or 2. However, alkali halides, such as lithium chloride or sodium chloride, can also be used successfully for this addition reaction; it also takes place without catalysts.

in the manufacture of dialcohols of formula (I) in which the sum of m and n is greater than 2, it is preferable to start from the simple dialcohols of formula (I) in which m and n are each 1, and to add further styrene oxide to both OH groups of this compound in the presence of acid catalysts The mononuclear N-heterocyclic compounds of formula (lI) used for the manufacture of the new styrene oxide addition products of formula (I) are above all hydantoin, hydantoin derivatives, barbituric acid, barbituric acid derivatives, uracil, uracil derivatives, dihydrouracil and dihydrouracil derivatives, and also parabanic acid.

Hydantoin and its preferred derivatives correspond to the general formula wherein R and R each denote a hydrogen atom or a lower alkyl radical with l to 4 carbon atoms, or

wherein R, and R together form a tetramethylene or pentamethylene radical. Hydantoin, S-methylhydantoin, S-methyl-S-ethylhydantoin, 5-npropylhydantoin, 5-isopropyl-hydantoin, 1,3-diazaspiro (4.5)-decane-2,4-dione, 1,3'diaza-spiro(4.4)- nonane-2,4-dione and preferably 5,5-dimethylhydantoin may be mentioned.

Barbituric acid and its preferred derivatives correspond to the general formula wherein and independently of one another each denote a hydrogen atom, an alkyl radical, an aJkenyl radical, a cycloalkyl radical or cycloalkenyl radical, or

wherein R and R both denote hydrogen atoms or one of the two radicals denotes a hydrogen atom and the other radical denotes a methyl group.

Uracils of formula (V) are uracil itself, and also 6- methyl-uracil and thymin S-methyl-uracil).

Dihydrouracil 2,4-dioxo-hexahydropyrimidine) and its preferred derivatives correspond to the general formula:

wherein R and R both denote a hydrogen atom or identical or different alkyl radicals, preferably alkyl radicals with 1 to 4 carbon atoms, and R and R independently of one another each denote a hydrogen atom or an alkyl radical.

Preferably, in the above formula, both radicals R and R denote methyl groups, R denotes a hydrogen atom or a lower alkyl radical with l to 4 carbon atoms and R denotes a hydrogen atom. The following may be mentioned: 5,6-dihydrouracil, 5,5-dimethyl-5,6- dihydrouracil (2,4-dioxo-5 ,S-dimethylhexahydropyrimidine) and 5,5-dimethyl-6-isopropyl-S,6- dihydrouracil (2,4-dioxo-5 ,5-dimethy1-6-isopropylhexahydropyrimidine EXAMPLE 1 Manufacture of 1,3-di-(B-hydroxy-B-phenylethyl- 5,5-dimethylhydantoin A mixture of 512.6 g of 5,5-dimethylhydantoin (4.0 mols), 500 ml of dimethylformamide and 3.4 g of lithium chloride is stirred at 120C. 1,058.0 g of styrene oxide (8.8 mols) are added dropwise at 119-122C, over the course of 2 hours, to this clear pale yellow solution. The reaction is slightly exothermic, so that the heating bath can periodically be removed. After the dropwise addition, the mixture is stirred for a further 3 hours at 120C. The clear, orange-coloured solution is concentrated at 85C on a rotary evaporator under a waterpump vacuum and is subsequently dried at 90C (0.1 mm Hg). 1,473.0 g of a clear, orange-brown, highly viscous resin (100 percent of theory) are obtained.

This crude 1,3:di-(B-hydroxyfi-phenylethyl)-5,5- dimethylhydantoin can be purified by vacuum distillation. percent of the material employed distil at 260C under 0.3 mm Hg. A colourless to pale yellow, viscous liquid is obtained, which on cooling solidifies to a glassy brittle mass. This substance is pure 1,3-di-(B- hydroxy-B-phenylethyl)-5,S-dimethylhydantoin.

Elementary analysis shows found calculated 68.46% C 68.46% C Determination of the molecular weight by vapour pressure osmometry in acetone shows a molecular weight of 365 (theory 368.42).

The infra-red spectrum (material ground with Nujol) shows, inter alia, through the presence of intensive ab sorptions at 3,450 cm (OH), 1,758 cm and 1,685 cm (C=O) and 697 cm, that the desired substance is obtained.

The proton-magnetic resonance spectrum (60 Mc H-NMR recorded in CDCl at 35C with tetramethylsilane (TMS) as an internal standard) proves the structure shown below, through the presence of the signals, quoted below, for the 24 protons present:

This at the same time shows that the structural element is not present, since in this element the OH signal would have to be a triplet; furthermore, the proton on the tertiary C atom would in this case be expected at about 8 3.80, and furthermore the protons of the -CH group would then have to appear at about 8 A mixture of 184.24 g of 5,5-dimethyl-6-isopropyl- 3 .0. 5 ,6-dihydrouracil 2,4-dioxo-5 ,5-dimethy1-6- The new substance thus corresponds to the following isopropylhexahydropyrimidine) (1 mol), 1.27 g of lithstructure ium chloride and 1 litre of dimethylformamide is stirred 5 at 150C. 252.5 g of styrene oxide (2.1 mols) are slowly added dropwise over the course of 3 hours. After the CH3 0 dropwise addition, the mixture is stirred for a further 3 E hours at 150C. The light brown, slightly cloudy solution is clarified by Hg. and concentrated on a rotary uoecHiN NoHiiJ-01r .10 evaporator at 80C under a waterpump vacuum, and

I subsequently dried at 80C/0.1 mm Hz. 349 g of an orange-brown, clear and transparent slightly tacky,

solid residue (82.5 percent of theory) are obtained.

EXAMPLE 2 The infra-red spectrum shows, through the absence of N-H frequencies and through OH absorptions, that 1l3'd"(fihydroxy'fi'phenylethyl*6 l,3-di-(B-hydroxy-B-phenylethyl)-5,5-dimethyl-6- A solution of 63 g of 6-methyluraci1 (0.5 mol) and isopmpyhs6'dihydrouracil has been produced as I 0.5 g of lithium chloride in 800 m1 of dimethylformamide is stirred at 120C. 132.2 g of styrene oxide (1.1 20 mols) are added dropwise, with stirring, over the course of 2 hours. After the dropwise addition, the mixture is stirred for a further 2 hours at 130C. The resulting clear, yellow solution is concentrated on a rotary evaporator at 80C, under a water-pump vacuum, and l l is subsequently dried at 80C 0.1 mm Hg). 180 g (98.3 fi g'gii, 'fi; ggf, f percent) of crude 1,3-di-(B-hydroxy-B-phenylethyl)-6- A Solution 101 g f the 3 methyluracil are obtained in the form of a clear, transphenylethyl) 5,5 dimethy|hydamoin (0274 mol) Parent, hght y i Sohd For Purification the manufactured according to Example 1, in 500 ml of di- Productis reerystalhseh from ethanol/Water; 1 get oxane is mixed with 3.0 m1 of 47 percent strength P e Product e Ohtalhed; the meltlhg P 15 about boron fluoride diethyl etheratesolution in diethyl ether 139.5 141C. I and stirred at 80C, whereupon a claret solution results. Elementary ahalysls Shows H (Calculated, 197.5 g of styrene oxide (1.642 mol) are slowly added The ihh'a'red Spectrum Shows inter aha, dropwise to this solution over the course of 45 minutes. through the absence of the frequencies and The reaction is so strongly exothermic that the heating through the Presence of an intensive absorption of bath is removed, and the contents of the flask reach a 3,340 i that the desired Substance is Obtaihedmaximum temperature of 87C. After the addition of The Proton-magnetic resonance Spectrum MC styrene oxide, the mixture is further stirred until the NNMR, recorded in CDCla at with TMS as the batch has cooled to room temperature. The pH of the standard) shows, through the following signals, that the 40 solution, which is now pale yellow, is 4. The pH value new dialcohol has the structure given below: According i adjusted to 7.0 by means of 30 percent strength soto integrati n. 22 pr s are present y, 2 dium hydroxide solution. The solution is concentrated to 250 ml on a rotary evaporator and then cooled EXAMPLE 4 Manufacture of l,3-di-(B-hydroxy-B-phenylethoxy- 3 protons-..

(10C) and filtered to remove inorganic constituents. l Thereafter the filtrate is completely concentrated CH3 (60C/waterpump vacuum) Drying takes place at 9 Pmhms are-50450 k 90C/0.1 mm Hg. 245 g of a slightly yellowish, clear,

C I solid resln are obtained. The increase from 101 g to 245 g shows that 4 mols of styrene oxide have reacted mpmns 6:73, H p mol of starting d 2XH@ H H Elementary analysis shows: found calculated (for 4 mols of styrene O oxide per mol of diol) H 75.1%C 75.1%C l A I 6.6% H 6.6% H H-0oH-oHi-N N-CH2(]JOH 33% N 33% N e .7. M... v..." H30 \C \O Thls who can also be determined by means of the proton-magnetic resonance spectrum (60 EXAMPLE 3 Mc HNMR) from the lntegratlon who of the methyl protons to the aromatic protons; here again it is found Manufacture Of i -(fiy y-fi-p y y that essentially the following is the correct average 5,5-dimethyl-6-isopropyl-5,6-dihydrouraci1 t t r EXAMPLE Manufacture of 3-(fi-hydroxy-B-phenylethyl)-5,5-

dimethylhydantoin A mixture of 508 g of 5,5-dimethylhydantoin (3.96 mols), 5.05 g of lithium chloride and 550 ml of dimethylformamide is stirred at 125C. 480.6 g of styrene oxide (4.0 mols) are added dropwise thereto over the course of 90 minutes. Thereafter the mixture is stirred for a further 180 minutes at 125C. The reaction mixture is filtered and concentrated at 90C on a rotary evaporator under a waterpump vacuum, and the residue is subsequently dried to constant weight at 90C under 0.1 mm Hg. 983 g (99.9 percent theory) of a yellow-white crystal mass are obtained. For purification, the product can be recrystallised from acetone. Colourless, glistening, fine crystals are obtained, which melt at 146146.5C. Elementary analysis shows the following values:

found calcglatgd 62.86 C 62.89 C 6.4 H 6.5 H I 1.5 N 11 3 N The infra-red spectrum (material ground with Nujol) shows the 01-1 absorption at 3,430 cm, and the carbonyl frequencies appear at 1,760, 1,730 and 1,690 cm.

The proton-magnetic resonance spectrum (60 Mc H-NMR, recorded in CDCl at 35C, against TMS) shows the following signals:

aa;....;i 1" '6=1.32 ks'ihg1)....f.f CH3 3H 8=3.754.00 (Multipiet) 1;IClh and OH 111. 6=5.0 Multi let) 1 1H 6=6.50 (Multlplet) N1H 5H 5=7.34 (Singlet) Aromaticprotons.

in total, 16 protons are thus found (theory 16).

The mass spectrum is also in accord with the structure given below. The molecule-ion is found at 248, which agrees with the theoretical molecular weight of 248.3. Furthermore, the following characteristic fragments are found: 231 (248- OH): 171 (238-C H 142 (248C H CO) 127 (=142--CH etc.

The new monoalcohol thus has the following structure EXAMPLE 7 Manufacture of 1,3-di-(B-hydroxy-B-phenylethyl)-5- isopropylhydantoin A mixture of 60.08 g of 5-isopropylhydantoin (0.4226 mol), 300 ml of dimethylformamide and 0.5 g of lithium chloride is stirred at 120C. 132.1 g of styrene oxide (1.0995 mols) are added dropwise thereto over the course of 3 hours. Thereafter the mixture is allowed to continue reacting for a further 180 minutes at 130C. The filtered reaction mixture is concentrated at C on a rotary evaporator under a waterpump vacuum and is subsequently dried to constant weight at C/0.1 mm Hg. 161 g of a light yellow crystal mass (99.6 percent of theory) are obtained, and this mass can be purified by recrystallisation from ethanol. Elementary analysis shows 687 H (theory 6.85 H) and 7.45 N (theory 7.33 N); the proton-magnetic resonance spectrum is also in agreement with the fol lowing structures:

EXAMPLE 8 Manufacture of 1 ,3-di-(B-hydroxy-B-phenylethyl )-5- ethyl-S-phenylbarbituric acid A mixture of 1 16.12 g of 5-ethyl-5-phenylbarbituric acid (0.5 mol), 0.5 g of lithium chloride and 500 m1 of dimethylformamide is stirred at C. 132.16 g of styrene oxide (1.1 mols) are added dropwise to this clear solution over the course of 75 minutes. The mixture is then further left at C for 205 minutes, cooled to 50C, filtered and concentrated at 75C on a rotary evaporator under a waterpump vacuum, and thereafter dried to constant weight at 85C and 0.1 mm Hg.

235 g of a clear, light yellow, viscous substance (99.3 percent of theory) are obtained. The proton-magnetic resonance spectrum (60 Mc H-NMR, recorded in CDCl:, at 35C, against TMS) shows, inter alia, through the integration ratio of the signals at 5 0.8 (multiplet of the CH -CH group) and 8 =7.3 (multiplet of the aromatic protons) of 3/15, that the substance has the following formula:

We claim: 1. A monoalcohol or dialcohol of the formula C i J m n wherein R, R", R and R"" each represents a mem ber selected from the group consisting of alkyl with l to 4 carbon atoms, alkenyl with 2 to 4 carbon atoms, cyclohexyl, cyclohexenyl and phenyl, or when the residue Z represents the formulae R and R" together can also form a member selected from the group consisting of divalent tetramethylene and pentarnethylene ring, and m and n each represents an integar having a value of 0 to 3 with the sum of m and n having to be at least 1.

2. A compound as claimed in claim 1 which is l,3-di- (B-hydroxy-B-phenylethyl)-5,S-dimethylhydantoin.

3. A compound as claimed in claim 1 which is 1,3-di- (B-hydroxy-B-phenylethyl )-6-methyluracil.

4. A compound as claimed in claim 1 which is 1,3-di- (B-hydroxy-B-phenylethyl)5,5-dimethyl-6-isopropyl- 5,6-dihydrouracil.

5. A compound as claimed in claim 1 which is 1,3-di- (B-hydroxy-B-phenylethoxy-B-phenylethoxy-B- phenylethyl)-5,5-dimethylhydantoin.

6. A compound as claimed in claim 1 which is 3-(B- hydroxy-B-phenylethyl )-5 ,5 -dimethylhydantoin.

7. A compound as claimed in claim 1 which is l,3-di- B-hydroxy-B-phenylethyl )-5 -isopropylhydantoin.

8. A compound as claimed in claim 1 which is 1,3-di- B-hyd roxy-B-phenylethyl )-5 -ethyl-5 -phenylbarbitun'c acid. 

1. A MONOALCOHOL OR DIALCOHOL OF THE FORMULA
 2. A compound as claimed in claim 1 which is 1,3-di-( Beta -hydroxy- Beta -phenylethyl)-5,5-dimethylhydantoin.
 3. A compound as claimed in claim 1 which is 1,3-di-( Beta -hydroxy- Beta -phenylethyl)-6-methyluracil.
 4. A compound as claimed in claim 1 which is 1,3-di-( Beta -hydroxy- Beta -phenylethyl)-5,5-dimethyl-6-isopropyl-5,6-dihydrouracil.
 5. A compound as claimed in claim 1 which is 1,3-di-( Beta -hydroxy- Beta -phenylethoxy- Beta -phenylethoxy- Beta -phenylethyl)-5,5-dimethylhydantoin.
 6. A compound as claimed in claim 1 which is 3-( Beta -hydroxy-Beta -phenylethyl)-5,5-dimethylhydantoin.
 7. A compound as claimed in claim 1 which is 1,3-di-( Beta -hydroxy- Beta -phenylethyl)-5-isopropylhydantoin.
 8. A compound as claimed in claim 1 which is 1,3-di-( Beta -hydroxy- Beta -phenylethyl)-5-ethyl-5-phenylbarbituric acid. 